Metastasis is the main cause of
cancer treatment failure and death. However, current
therapies are designed to impair
carcinoma metastasis mainly by impairing initial dissemination events. CXCR4 is a
G-protein coupled receptor that exclusively binds its
ligand CXCL12, which can stimulate cells to metastasize to distant sites. As the antagonist of
chemokine receptor CXCR4,
Peptide S exhibited anti-
metastasis effect. In order to enhance treatment efficiency through destroying primary
tumors and inhibiting their
metastases, we combined PEGylated
doxorubicin-loaded
liposomes (DOX-Lip) with anti-
metastasis Peptide S for
tumor therapy for the first time. DOX-Lip exhibited similar cytotoxic activity compared to free DOX in vitro, and
Peptide S showed no toxic effect on cell viability. However, the
Peptide S sensitized CXCR4-positive B16F10
melanoma cells to DOX-Lip (5 μM) when cocultured with stromal cells (50.18±0.29% of viable cells in the absence of
Peptide S vs 33.70±3.99% of viable cells in the presence of
Peptide S). Both
Peptide S and DOX-Lip inhibited the adhesion of B16F10 cells to stromal cells. We further confirmed that the inhibition of phosphorylated Akt (pAkt) by
Peptide S played a key role due to the fact that activation of pAkt by DOX-Lip promoted resistance to
chemotherapy. Migration and invasion assays showed that DOX-Lip enhanced anti-
metastasis effect of
Peptide S in vitro because of the cytotoxicity of
doxorubicin. In vivo studies also showed that the combined treatment with DOX-Lip and
Peptide S not only retarded primary
tumor growth, but also reduced lung
metastasis. Both the DOX-Lip and DOX-Lip+Peptide S exhibited even more outstanding
tumor inhibition effect (with
tumor growth inhibition rates of 32.1% and 37.9% respectively). In conclusion, our combined treatment with CXCR4 antagonist and
liposomal doxorubicin was proved to be promising for antitumor and anti-
metastasis therapy.